The applicant states that arrhythmias may arise through initiation from an ectopic focus, from early or delayed afterdepolarizations, or from micro- or macro-reentry, but the way in which spatial inhomogeneities in action potential properties, tissue geometry, and intercellular coupling lead to the initiation of arrhythmias remains poorly understood. The applicant's overall approach is to combine the analytical power of studying single isolated myocytes with the ability to recombine these cells into pairs of cells with the same or different properties, or to allow these cells to interact with an interactive computer model in order to understand how the geometrical properties, intercellular resistance and modulation of membrane properties lead to variable conduction delay, success or failure of conduction, and rhythmic or non- rhythmic activation. Using coupled ventricular cells the applicant will test the hypotheses that, for ventricular cells which are partially uncoupled, the calcium current is increased in the leader cell but, not in the follower cell, during the conduction process and that pharmacological interventions which modulate the L-type calcium current have significant effects on conduction delay and conduction success, especially for premature excitation. Using cells from the AV node, the applicant will test the hypothesis that conduction failure or delay involves the ratio of the current which can be supplied by the leading cell (the source current) to that required for excitation of the following cell (the sink current) with interventions such as premature stimuli, rapid pacing, autonomic effects and pharmacological modulation. Using ventricular cells with afterdepolarizations, the applicant will test the hypothesis that the minimal size of the automatic focus will be determined by the input resistance of the quiescent cell, the coupling resistance, and b-adrenergic stimulation. For experiments on the Purkinje-Ventricular Muscle Junction the applicant will test the hypothesis that modulation of L-type calcium current will strongly affect the conduction process, especially for premature excitation.